Is PREP p.Ile538Thr (c.1613T>C) pathogenic?

PREP p.Ile538Thr (c.1613T>C) is classified Uncertain significance in PREP (ClinVar, Single submitter, 1 submitter; last evaluated 2024-01-16). AlphaMissense: ambiguous (0.3444); Ultra-rare (popmax 0.0333%, amr).

How common is PREP p.Ile538Thr (c.1613T>C) in the general population?

PREP p.Ile538Thr (c.1613T>C) is ultra-rare (popmax 0.0333%, amr) (gnomAD).

What do computational predictors say about PREP p.Ile538Thr (c.1613T>C)?

AlphaMissense predicts ambiguous (score 0.3444) — an in-silico prediction, not a clinical call.

PREP p.Ile538Thr

c.1613T>C · rs201312087 · VCV3218536

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3444 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0333%, amr)

Computational evidence

Protein change
AlphaMissense	0.3444	ambiguous
REVEL	0.422	indeterminate
SaProt	LLR -9.19	tolerated
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 2.7, phastCons 1
Overall
CADD	27.4	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0333% Admixed American · 20/60,030 alleles

Filtering AF 0.0221% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0184%

Overall 0.00155% 25/1,614,192 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0333%	3,001
Remaining individualsnot grpmax-eligible	0.0032%	31,254
African / African-American	0.00133%	75,058
European (non-Finnish)	0.000169%	590,012

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: PREP
Protein: p.Ile538Thr
Coding: c.1613T>C
MANE Select: NM_014889 · reported on NM_002726
dbSNP: rs201312087
Type: single nucleotide variant
Location: chr6:105282519 (GRCh38)
Structure: AlphaFold pLDDT 94.44 · 8 PDB
Residue 538: an α-helix; a disulfide bond

Full PREP gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

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PITRM1 p.Ala887Val Uncertain significance ★★ ⚠ same type
PITRM1 p.Ala942Val Uncertain significance ★★ ⚠ same type
PITRM1 p.Ala965Thr Uncertain significance ★★ ⚠ same type
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Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/prep-p-ile538thr (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown